Project 461366

One in 5 Canadians and almost 350 million people worldwide suffer from major depressive disorder (MDD). Depression has devastating consequences on human health, affecting all facets of life. Though treatment options exist, there remains a barrier to the precise diagnosis, correct matching of therapeutics to the broad spectrum of disease manifestation, and importantly, to the prevention of initial onset. In general, women are underrepresented in neurobiology research, yet they are reported to be at a two- to three- times greater risk of developing major depression, highlighting an important need, not only for increased inclusion in research but for studies to pay specific attention to sex. Given the complexity of this disease, we need to use the highest precision and resolution possible. Though clinical studies have pointed to the differences in occurrence, presentation, and response to pharmacotherapy, we still lack the clear molecular basis of these traits. Past studies have used transcriptomic approaches to advance the understanding of MDD's biological etiology, however, these studies are hindered by bulk tissue which represents a mixture of brain cells, introducing confounding effects from cellular composition, and masking subtle gene effects. Our aim is to uncover the molecular features underlying sex-specific cellular phenotypes and networks to discern how susceptibility and development of MDD differ between sexes. This project will examine individual brain cells from people with a history of MDD (and matched controls) to disentangle the contribution of cells, and their networks, within and across brain regions, to given depressive traits. This resolution will allow us to define sex- and disease-specific molecular and cellular networks that can provide more precise information for intervention and therapeutics. Identifying disrupted molecular and cellular networks will bring us one step closer to identifying causal biological changes associated with MDD.